This resulted in doses for the five individuals of between 0.54 and 0.66 mg/kg body weight. The DPHP dose was considerably below the lowest NOAEL (no observed adverse effect level) for DPHP (BfR Opinion No., 2011 and Bhat et al., 2014) and comparable to the DINP (Koch and Angerer, Erismodegib molecular weight 2007) or DINCH®

dose levels (Schütze et al., 2014) of previous human metabolism studies. The DPHP dose was several orders of magnitude above exposure levels expected for the general population. Stable-isotope labeled DPHP-d4 was used to exclude possible background exposures. Volunteers were dosed at the Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr-Universität Bochum (IPA), frozen samples of urine were shipped to Currenta for quantification of the metabolites. The first urine samples were collected prior to dosage at 10:00 a.m. followed by subsequent urine samples collected over 48 h post-dosing. The volunteers recorded the

time of the void of each sample. The urine volume of each individual sample was determined as the difference between the weight of the filled and the empty container. In all, we obtained 122 urine PARP inhibitor samples, i.e., between 20 and 29 samples from each volunteer. The total 48 h urine volume ranged from 4133 to 8298 ml, depending on the volunteer. All urinary samples were frozen at −18 °C immediately after delivery. The study was carried out in accordance with the code of ethics of the World Medical Association (Declaration of Helsinki) and was approved by the ethical review board of the Medical Faculty of the Ruhr-University Bochum

(Reg. No.: 4022-11). The study design was presented to the volunteers in written form, and all participants provided written informed consent. Acetonitrile (supra solv), methanol (supra solv), glacial acetic acid (p.a.) and hydrochloric acid 37% (p.a.) were purchased from Merck, Darmstadt, Germany. Ammonium acetate (p.a.) was purchased from Fluka, Taufkirchen, Germany. Formic acid (99%, ULC/MS) was purchased from Biosolve B.V., Valkenswaard, The Netherlands. Water from a millipore water cleaning system was used and β-glucuronidase from Escherichia coli K12 was purchased from Roche, Mannheim, Germany. DPHP-d4 was provided by BASF SE. The following standards Ponatinib were synthesized at the Institut für Dünnschichttechnologie e.V. (IDM), Teltow, Germany: mono-2-(propyl-6-hydroxy-heptyl)-phthalate (OH-MPHP), mono-2-(propyl-6-oxo-heptyl)-phthalate (oxo-MPHP), mono-2-(propyl-6-carboxy-hexyl)- phthalate (cx-MPHxP), mono-2-(propyl-6-hydroxy-heptyl)-phthalate-d4 ring deuterated (OH-MPHP-d4), mono-2-(propyl-6-oxo-heptyl)-phthalate-d4 ring deuterated (oxo-MPHP-d4), and mono-2-(propyl-6-carboxy-hexyl)-phthalate-d4 ring deuterated (cx-MPHxP-d4). The purity of all compounds was determined by 1H-NMR and was ≥95%.